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Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways.

Green, JA; Dholakia, S; Janczar, K; Ong, CW; Moores, R; Fry, J; Elkington, PT; Roncaroli, F; Friedland, JS (2011) Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways. J Neuroinflammation, 8. p. 46. ISSN 1742-2094
SGUL Authors: Friedland, Jonathan Samuel

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Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

Item Type: Article
Additional Information: © 2011 Green et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Anti-Inflammatory Agents, Non-Steroidal, Caspase 8, Culture Media, Conditioned, Extracellular Signal-Regulated MAP Kinases, Humans, Matrix Metalloproteinase 2, Microglia, Monocytes, Mycobacterium tuberculosis, NF-kappa B, Sesquiterpenes, Signal Transduction, Tuberculosis, Central Nervous System, Tumor Necrosis Factor-alpha, p38 Mitogen-Activated Protein Kinases, Microglia, Monocytes, Humans, Mycobacterium tuberculosis, Tuberculosis, Central Nervous System, Sesquiterpenes, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Tumor Necrosis Factor-alpha, NF-kappa B, Anti-Inflammatory Agents, Non-Steroidal, Culture Media, Conditioned, Signal Transduction, Matrix Metalloproteinase 2, Caspase 8, Science & Technology, Life Sciences & Biomedicine, Immunology, Neurosciences, Neurosciences & Neurology, NERVOUS-SYSTEM TUBERCULOSIS, NECROSIS-FACTOR-ALPHA, METALLOPROTEINASE GENE-EXPRESSION, HUMAN CANCER-CELLS, MATRIX METALLOPROTEINASES, CEREBROSPINAL-FLUID, IN-VITRO, EPITHELIAL-CELLS, GELATINASE-B, IFN-GAMMA, 1103 Clinical Sciences, 1109 Neurosciences, 1107 Immunology, Neurology & Neurosurgery
Journal or Publication Title: J Neuroinflammation
ISSN: 1742-2094
Language: eng
11 May 2011Published
11 May 2011Accepted
Publisher License: Creative Commons: Attribution 2.0
Project IDFunderFunder ID
DHCS/06/05/012Department of Health
G0500385Medical Research Council
PubMed ID: 21569377
Web of Science ID: WOS:000291591200001
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